Highly active antiretroviral therapy (HAART) has led to sustained suppression of HIV-1 in the blood of many infected patients, but HAART does not eliminate virus from memory CD4 plus cells in peripheral blood. Viral recovery has also been demonstrated in other reservoirs of infection, including the male genital tract. However, limited knowledge is known about viral populations in the male genital tract, even though semen is a major source of sexually transmitted virus. The major aim of this project is to compare the genetic diversity of HIV-1 in semen and blood using the V3 loop region of the envelope (env) gene. The V3 domain is the most hyper-variable region in the whole HIV-1 genome and, hence, is an excellent marker of continuous viral evolution. The V3 sequences of viruses from semen will be amplified, cloned, sequenced, and compared to similar regions in blood. Paired samples of semen and blood will be analyzed longitudinally from several different patient populations: patients with chronic infection both prior to and following HAART, patients with acute infection targeted for "early" aggressive treatment with HAART, and patients with vigorous responses to HAART. These studies will determine whether longitudinal differences in the V3 region are separately selected for in semen and blood in the presence or absence of drug pressure; whether viral variants in blood and semen migrate between these two compartments; and, whether HAART during either chronic infection or primary HIV-1 infection can modify the genetic evolution in the V3 loop, and, theoretically, the whole HIV-1 genome. The PI feels that this research proposal and his ancillary didactic pursuits will help him acquire skills and expertise needed to successfully pursue a career in HIV-1 research. His ultimate career goal is to become an independent investigator of virology at an academic setting, where he could pursue bench-top research for the majority of his time. Working in an academic environment, he also hopes to provide clinical care to patients infected with HIV-1 and maintain a minor role as a hospital consultant in clinical infectious diseases. The PI also plans to remain involved in the clinical and basic research teaching and training of medical students, housestaff, and postdoctoral fellows. Support from a K08 research career award will assist in the completion of this proposal and help the applicant realize his career goals.